June 16, 2026 | News | Living with MS MS Research MS Treatments

The New MS – The Future of MS

Part 3 of 3
Read Part 1, Part 2

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The perspective on MS has dramatically changed over the past decade (see also Part 1). The initial focus of treatment was on reducing relapses and inflammatory lesions in the brain. But it is now apparent that targeting this form of inflammatory disease activity does not adequately address the underlying changes that cause long-term disability. An analogy would be taking a medication to relieve fever caused by an infection rather than treating the infection itself. To extend the analogy, frequent relapses may be akin to a higher temperature: both can be damaging in themselves, but they may be more important as indicators of the severity of the underlying problem. So while it is important to reduce relapses, relapse reduction alone is not sufficient to maintain physical and mental functioning over the longer term.

It is now recognized that most disability worsening occurs somewhat independently of inflammatory activity. Neurological disability in MS originates in the brain – so that needs to be the next battlefield. An important treatment target are chronic active lesions, hot spots where the inflammation persists and does not shut down. As tissue gets damaged, immune cells called microglia attempt to clear away the debris. But as inflammation drags on, these microglia remain activated, gnawing away at healthy tissue and slowly expanding the size of the lesion, a process called smouldering inflammation.

Chronic active lesions are not the whole story of MS. There are other disease mechanisms that contribute to damage or prevent the damage from being repaired, and this complexity provides countless targets for MS medications. To take just one example, several drugs have used different approaches to promote remyelination. For example, the antihistamine clemastine showed early promise in stimulating the cells that produce myelin (Green and colleagues. Lancet 2017;390:2481-2489), but more recent studies raised safety concerns (Kocot and colleagues. J Clin Invest 2025;135:e183941). The cholesterol drug simvastatin appeared to preserve neurons and reduce brain atrophy in early testing, but failed to slow disability worsening in a phase III study (Chataway and colleagues. Lancet 2025;406:1611-1624). A novel therapy, opicinumab, was developed to target a protein in the brain that blocks myelination, but failed to show efficacy in the AFFINITY trial (Calabresi and colleagues. Mult Scler 2026;32:107-120).

Despite these setbacks, there are dozens of other potential medications currently being investigated. The hottest class of MS medications are BTK inhibitors, which were developed to target activated microglia. The first two candidates, evobrutinib and tolebrutinib, posted disappointing results and have been largely abandoned. Two other BTK inhibitors are waiting in the wings. Fenebrutinib has completed three trials and has shown mixed results. Two studies in relapsing-remitting MS reported a significant reduction in relapses and MRI lesions, but fenebrutinib was no better than Aubagio in slowing disability. The third study was in primary-progressive MS and showed that fenebrutinib was non-inferior to ocrelizumab in slowing disability. As for the second drug, remibrutinib, no results are available but preliminary data from the REMASTER and REMODEL studies will be presented later this year.

Also in development is PIPE-307, which is being studied in the VISTA trial as an add-on therapy to promote remyelination (Poon and colleagues. Proc Natl Acad Sci U S A 2024;121:e2407974121). The results have not been reported.

Future clinical trials
The unfortunate reality of drug development is that most treatments fail because of a lack of efficacy or unacceptable side effects. One of the challenges in studying novel therapies is how to define efficacy. If a medication is supposed to suppress relapses, you simply count the relapses with and without treatment. But how do you demonstrate that a drug reduces tissue damage, promotes remyelination, or reduces diffuse inflammation in the brain? Even if these benefits are seen, will this targeted effect have an impact on a person’s long-term functioning? Will it change the course of MS?

These issues have prompted researchers to discuss how best to run clinical trials in the future. For example, when assessing changes in disability, neurologists have used the Expanded Disability Status Scale (EDSS) for the past 40 years. But more recent trials have attempted to detect a more broadly-defined disability by using a wider array of tools, such as the Timed 25-Foot Walk (which measures walking speed), the 9-Hole Peg Test (which evaluates upper limb function) and the Symbol Digit Modalities Test (which tests cognitive function). Some studies also evaluate patient-reported outcome measures (PROs), which can detect hidden symptoms (such as MS fatigue or depression). The use of PROs can ensure that the effects of a drug are actually providing a benefit that is relevant to a person’s daily function and quality of life.

An increasingly important innovation is the use of biomarkers in trials and in the clinic. Some biomarkers, such as neurofilament-light (NfL), a measure of nerve damage, can determine if disease activity is severe and whether a treatment is working to reduce this damage. There is also a growing number of imaging techniques that can spot specific disease mechanisms, such as smouldering inflammation, expanding lesions and microglia activation. While the equipment needed for these investigations is not yet widely available, more clinics in the future will use these findings to better characterize the specific disease mechanism(s) that are active in individual people with MS at different times in their lives. Why MS manifests differently in people is not known. But it may be that a person’s genetics alter which disease components are active, and how well innate repair mechanisms are working in a given person.

MS comprises many disease processes, and together they contribute to an overall picture of how MS will express itself in an individual. As more is learned about these processes, doctors may be able to provide a cocktail of therapies – mixed together or provided in sequence – to target a specific type of damage as it occurs. The idea would be to adapt the therapy to the individual’s specific needs at specific times – which would usher in an era of a more truly personalized medicine.

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